The present invention, in some embodiments thereof, relates to surfaces having applied thereon therapeutically active agents and, more particularly, but not exclusively, to articles-of-manufacture such as medical devices having applied thereon a crystalline form of a therapeutically active agent.
Drug-eluting stents (DES) have become an accepted technology in intravascular intervention.
Examples of such drug-eluting stents are paclitaxel-eluting stents (TAXUS® stents, Boston Scientific), which inhibit the proliferation of SMCs, and sirolimus (rapamycin)-eluting stents (Cypher® stents, Cordis Corporation), which inhibit the inflammation response of the arterial wall. In these drug-eluting stents, a polymeric carrier is used for loading the anti-proliferative agent onto the stent. Unfortunately, such drug-eluting stents use polymers which are at least partially biostable, namely, remain stable and non-degradable under in vivo conditions, and can result in adverse effects, most commonly in-stent thrombosis. Consequently, DES patients are usually treated with anti-platelet therapy for a prolonged time period, which is also associated with adverse side effects and complications.
Development of drug-eluting stents devoid of polymeric carriers, or bearing a minimal amount of polymeric carriers, suffers from numerous limitations imposed by factors such as the poor adherence of therapeutically active agents to bare metal stents and the limited control of drug release (influenced, inter alia, by the drug's dissolution rate).
Manufacturing methodologies of drug-eluting stents are based mainly on mechanical processes such as spray and dip coating which tend to generate amorphous coatings that are poorly adhered to the surface, and have poor stability properties and fast drug release; related as a potential hazard [Levy et al., J Biomed Mater Res B Appl Biomater 2009, 91(1):441-451]. Moreover, many drugs in an amorphous phase, including rapamycin and paclitaxel, are chemically unstable, resulting in rapid degradation of the drug both under physiological conditions and under storage conditions, thus limiting their commercial and therapeutic value. Wessely et al. [Arteriosclerosis, Thrombosis, and Vascular Biology 2005, 25:748] teach a polymer-free stent coated with rapamycin by spray-coating the surface with a rapamycin solution, as well as a device for coating the stent before use.
WO 2010/086863 describes articles-of-manufacturing comprising a therapeutically active agent deposited onto a surface hereof, while at least a portion of the therapeutically active agent is in a crystalline form; as well as processes and apparatuses for preparing such articles-of-manufacturing by contacting a surface with a solution containing the therapeutically active agent, and cooling the surface to a temperature below a temperature of the solution.
Most of the studies conducted with crystalline drug in drug-eluting stents use polymeric carriers to facilitate adherence of crystalline drugs to surfaces.
WO 00/032238 teaches a stent having applied thereof a crystalline drug within or over a polymer coating which coats the stent.
WO 2006/063021 teaches a coating composition comprising a polymer and an active agent, wherein the active agent crystallizes following application of the coating composition.
U.S. Patent Application having Publication No. 20070154554 teaches a crystalline therapeutic agent encapsulated in a biocompatible polymer coating.
U.S. Pat. No. 7,282,213 teaches a method of applying a steroid to a surface of a medical device by depositing a solution of the steroid on the surface to form a crystalline coating, and heating the coating in order to form a coating that is better conformed to the surface.
WO 2006/105362 teaches antimicrobial metal-containing coatings.
U.S. patent applications having Publication Nos. 20080097618 and 20060210494 teach crystalline calcium phosphate coatings on medical devices. Additional background art includes WO 2007/011707 and U.S. patent applications having Publication Nos. 20020119178 and 20070134288.